CN109134269A - A kind of synthesis of micro passage reaction according to promise Gray's intermediate method - Google Patents
A kind of synthesis of micro passage reaction according to promise Gray's intermediate method Download PDFInfo
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- CN109134269A CN109134269A CN201810865459.6A CN201810865459A CN109134269A CN 109134269 A CN109134269 A CN 109134269A CN 201810865459 A CN201810865459 A CN 201810865459A CN 109134269 A CN109134269 A CN 109134269A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
- C07C209/36—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
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Abstract
A kind of synthesis of micro passage reaction belongs to the antithrombotic reagent synthesis technical field in organic synthesis according to the method for promise Gray's intermediate.For yield in traditional Hydrogenation reaction kettle synthesis process, low, purity difference, easily generation heavy explosion generate the problems such as dangerous, high temperature lower reaction time length causes degradation, catalyst recovery number is low, the present invention provides a kind of synthesis of micro passage reaction according to the method for promise Gray's intermediate, after raw material 4- nitro-phenylamino t-butyl formate is mixed with organic solvent and precious metal palladium supported catalyst, react in micro passage reaction preparing according to promise Gray intermediate (4- aminophenyl) t-butyl carbamate with hydrogen.The present invention is suitable for preparation and large-scale production according to promise Gray's intermediate.
Description
Technical field
The present invention relates to a kind of synthesis of micro passage reaction according to the method for promise Gray's intermediate, belongs to anti-in organic synthesis
Thrombus technical field of medicine synthesis.
Background technique
According to entitled N- (5- chlorothiophene -1- sulfonyl)-N'- { 4- [fluoro- 7- methylamino -2, the 4- dioxy of 6- of promise Gray's chemistry
Generation-Isosorbide-5-Nitrae-dihydro -3 (2H)-quinazolyl] phenyl } urea is by Novartis Co., Ltd of Switzerland and biotech company of U.S. Portola
The novel antithrombotic researched and developed jointly.It is a kind of novel blood platelet P2Y12 acceptor inhibitor according to promise Gray, is first and both may be used
It is oral again can intravenously administrable adenosine diphosphate (ADP) (ADP) receptor antagonist.Preclinical test and early studies in man show according to
Promise Gray has powerful antithrombotic acitivity, and rapid-action, effect is by force, this allows it to rapidly realize complete blood platelet suppression
System.Its chemical structure is as follows:
Wherein, compound (4- aminophenyl) t-butyl carbamate is the important intermediate synthesized according to promise Gray, about this
The synthesis of intermediate is mainly obtained by its precursor nitro compound by hydrogenating reduction, and chemical equation is as follows:
Restoring common method about the step nitro at present, mainly there are several types of 1) catalytic hydrogenation methods: with Pd, Ni, Pt
Equal heavy metals are catalyst, and hydrogen is that reducing agent carries out hydro-reduction reaction under high temperature and high pressure；2) metal deoxidization:
Iron is added under strong acid condition, zinc etc. has and restores nitro under the metallic high temperature of reproducibility；3) hydrazine hydrate reduction method: in graphite powder or
Restoring nitro using the reproducibility for being hydrazine hydrate in the presence of person's Raney's nickel is amido.
There are high pollution, high energy consumption, high risk, low economic value addeds for several methods about nitro reduction mentioned above
The disadvantages of, most production methods and production equipment all suffer from the risk being eliminated.
Summary of the invention
In order to solve low yield in traditional Hydrogenation reaction kettle synthesis process, purity difference, easily occur acutely it is quick-fried
Fried to generate the problems such as dangerous, high temperature lower reaction time length causes degradation, catalyst recovery number is low, the present invention provides one
Kind micro passage reaction synthesizes the method according to promise Gray's intermediate, and chemical equation is as follows:
The micro passage reaction core includes warm-up block, reaction module group and cooling module, in which: pre- hot-die
Block is connected with reaction module group, and reaction module group is connected with cooling module, and the reaction module group includes 1 unit process module
Or it is composed of more than two unit process block coupled in series；Synthesis according to promise Gray's intermediate method the following steps are included:
1) raw material 4- nitro-phenylamino t-butyl formate is added in organic solvent and is dissolved, it is negative that precious metal palladium is then added
Material I is delivered in the warm-up block of micro passage reaction and preheats as material I by carried catalyst, the mixture of acquisition, preheating
Enter reaction module group afterwards；The concentration of the 4- nitro-phenylamino t-butyl formate in organic solvent be 0.2mol/L~
0.3mol/L；The mass ratio of the 4- nitro-phenylamino t-butyl formate and precious metal palladium supported catalyst be 1:(0.01~
0.10)；
2) the reaction module group that hydrogen is delivered to micro passage reaction is being reacted with material I of the step 1) after preheating
Module group is reacted, and the reaction solution flowed out from cooling module is collected, and post-processing is obtained according to promise Gray intermediate (4- aminophenyl)
T-butyl carbamate；In the material I molar ratio of 4- nitro-phenylamino t-butyl formate and hydrogen be 1:(3.0~
3.5)。
It further limits, preheating temperature described in step 1) is consistent with the reaction temperature in step 2).
It is highly preferred that the concentration of 4- nitro-phenylamino t-butyl formate in organic solvent is 0.25mol/ in step 1)
L；The mass ratio of 4- nitro-phenylamino t-butyl formate and precious metal palladium supported catalyst is 1:0.05.
It is highly preferred that the molar ratio of 4- nitro-phenylamino t-butyl formate and hydrogen is 1 in the material I of step 2):
3.2。
It further limits, the step 1) organic solvent is methanol or ethyl alcohol.
It further limits, active noble metals palladium supported catalyst described in step 1) is palladium-Pd/carbon catalyst, palladium-molecule
One of sieve catalyst, palladium-zeolite catalyst, palladium-resin catalyst or a variety of compositions；When catalyst is a variety of group
It when conjunction, is mixed between each catalyst with arbitrary proportion, wherein precious metal palladium quality accounts for the 0.5%~5% of catalyst gross mass.
It further limits, the pressure of the step 2) reaction is 0.5MPa~1.5MPa.
It further limits, the temperature of the step 2) reaction is 60 DEG C~120 DEG C, preferably 90 DEG C.
It further limits, the temperature of the step 2) cooling module is 20 DEG C~30 DEG C.
Further limit, the total residence time of step 2) the material I and hydrogen in reaction module group be 10s~
50s。
It further limits, residue is added after referring to reaction solution recycling catalysts and solvents for the step 2) post-processing
Diluted hydrochloric acid dissolution then passes through active carbon decoloring, and the pH of filtrate NaOH solution regulation system is neutral to approaching, after product is precipitated
Target product (4- aminophenyl) t-butyl carbamate is obtained after being filtered, washed, drying.
Micro passage reaction of the present invention, also referred to as microreactor.Including warm-up block, reaction module group and cooling mould
Block, warm-up block are connected with reaction module group, and reaction module group is connected with cooling module, the unit process module of reaction module group
It is composed according to any serial or parallel connection such as charging rate, reactant concentration, reaction time, if reaction module group is by there is 1-8
A unit module is arbitrarily connected in series according to charging rate, reactant concentration, reaction time etc.；Such as the connection type in Fig. 2, with
For four unit process module composition reaction module groups, material I enters the of reaction module group 2 after the preheating of warm-up block 1
One group of unit process module, and the not preheated first group of unit process module for being directly entered reaction module group 2 of hydrogen,
The raw reaction of hybrid concurrency is carried out in one group of unit process module, and with the continuous entrance of hydrogen and material I, hydrogen and material
I flows to last group of unit process module from first group of unit process module, reacts in flow process, finally from cooling
Module outflow, the reaction solution of outflow are containing the solution according to promise Gray's intermediate, and cooling module is in order to by high temperature in the present invention
Feed liquid room temperature be down to by module facilitate processing.
Warm-up block can use the heart-shaped structure module of straight type structure or Two In and One Out in micro passage reaction of the present invention,
As shown in Figure 1, first group of unit process module can be using the microchannel with two entrances and one outlet in reaction module
Unit process module, referred to as Two In and One Out construction module, two of them entrance are respectively used to the entrance of hydrogen and entering for material I
Mouthful, second group of unit module to last group of unit module can be using the micro-channel units with an entrance and one outlet
Reaction module (referred to as single-entry single-out construction module), in which: Two In and One Out construction module is mainly used for hybrid reaction, Dan Jindan
Construction module is for extending reaction time and pyroreaction feed liquid being down to room temperature out.Above-mentioned warm-up block and reaction module
The order of connection of (Two In and One Out construction module+single-entry single-out construction module) are as follows: warm-up block, Two In and One Out construction module, list
Into single construction module out.Micro passage reaction further includes mashing pump and gas flowmeter in the present invention, and mashing pump A is for conveying object
Material I enters warm-up block 1, and hydrogen enters first group of unit process module of reaction module by gas flowmeter B.
The material of reaction module of the invention can be special glass, silicon carbide ceramics, the stainless steel for being coated with anti-corrosion layer
One or more of metal, politef, the Maximum safe pressure that can be born are 1.5~1.8MPa.
Step 2) the post-processing of the present invention will be after crude product diluted hydrochloric acid dissolution after referring to feed liquid recycling catalyst and solvent
By active carbon decoloring, NaOH solution crystallization is then added, product obtains target product according to promise after being filtered, washed, drying
Gray's intermediate (4- aminophenyl) t-butyl carbamate.
Beneficial effect
The present invention provides the catalytic hydrogenation synthetic technology that a kind of essential safety and environmentally protective nitro are reduced to amino,
This method utilizes micro passage reaction (being also called microreactor) technology to complete a kind of synthesis of catalytic hydrogenation reaction according to promise for the first time
Gray's intermediate (4- aminophenyl) t-butyl carbamate.
The common reducing agent of catalytic hydrogenation has formic acid, ammonium formate, hydrogen etc., among these hydrogen due to it is cheap,
For the features such as side reaction is few, Atom economy is high using very extensive, nitro hydro-reduction is that reducing agent is mainly secondary according to hydrogen
Product is water, does not generate other trade wastes in the case where solvent and catalyst reaction recycle, is extremely to mention at present
A kind of green, the production method of environmental protection advocated.But this kind of hydrogenation for having hydrogen to participate in is generally required in Pd, Pt, Ni etc.
It could be completed under the action of precious metal catalyst, since this kind of catalyst can not be dissolved in reaction dissolvent, catalytic hydrogenation is anti-
It should belong to typical airwater mist cooling hybrid reaction, in the case where traditional mixing plant gradually amplifies, three-phase mixing efficiency
It is very low, therefore catalytic hydrogenation reaction must carry out under long-time high temperature and pressure mostly, otherwise it is difficult to ensure that raw material is completely anti-
It answers.And the inflammable and explosive attribute of hydrogen inherently to be easy to send out if occurring hydrogen gas leakage or temperature control in reaction process
Raw production accident, therefore, such hydrogenation is defined as " high-risk " chemical reaction in large-scale commercial process, and
The reaction time too long under high temperature also results in the by-product that a large amount of degradation and over-hydrogenation are generated in system simultaneously, influences most
The purity and yield of finished product adhere to noble metal catalyst on the activated carbon in reaction process as the originals such as excessive friction
It is constantly reduced because active, recovery difficulty becomes larger.
Micro passage reaction set forth in the present invention, can be very due to the difference of design concept and stock size operation equipment
Good overcomes disadvantage mentioned above, and advantage can be summarized as follows:
1) micro passage reaction characteristic size is small, and heat transfer, mass transfer ability on unit plane, reaction rate significantly increase.Instead
It can be shorten to 30 seconds or so between seasonable, energy consumption is greatly reduced；
2) the distinctive online falling temperature technique of reactor, heat can be exported rapidly in time, and reaction temperature can be effective
The characteristics of control in safe range, is preferably minimized risk out of control, while continuous flow is reacted, even if accident occurs, due to
Online chemical volume is few, caused by injure and also can be ignored；
3) accurately controls reaction time, quick mixing, the fast reaction, fast cooling of material is realized, to have
The pyrolytic for reducing raw material and product of effect, improves the yield of reaction and the quality of product；
4) the shorter residence time makes the surface texture of catalyst there is no very big change, retains to greatest extent
The activity of catalyst, experimental result show that catalyst still has very high activity, the economy of catalyst after recycled 8 times
Cost is greatly reduced；
5) microchannel reaction system present modular structure, good portability, it can be achieved that product with using disperse construction and just
Ground production supplies and can adjust production according to market situation swap modules quantity, have very high operating flexibility.
Detailed description of the invention
Fig. 1 is the module material circulation duct shape and structure schematic diagram of organic glass material micro passage reaction, wherein (a)
(b) it is cardioid Two In and One Out module for the single-entry single-out module of cardioid, (c) is straight pattern block.
Fig. 2 is catalytic hydrogenation reaction process and micro passage reaction connection relationship diagram, and wherein A is mashing pump, and B is gas
Flowmeter body, 1 is straight type warm-up block, and 2 be cardioid Two In and One Out reaction module, and for hybrid reaction after preheating, 3-5 is respectively
The single-entry single-out reaction module of cardioid, 6 be the single-entry single-out module of heart-shaped structure, the cooling for pyroreaction feed liquid.
Specific embodiment
In following embodiments, used micro passage reaction includes warm-up block, reaction module group and cooling module, such as
Shown in Fig. 1 and Fig. 2, in which: warm-up block is connected with reaction module group, and cooling module is connected with reaction module group, reaction module
Group includes 1 unit process module or is composed of more than two unit process block coupled in series.
Material I and hydrogen mashing pump and gas flowmeter control in the present invention.When reaction is in micro passage reaction
When progress, warm-up block is the heart-shaped structure module of straight type structure or Two In and One Out；The preheating temperature and reaction temperature phase one
It causes, the reaction module is Two In and One Out or single-entry single-out heart-shaped structure module, and the order of connection is warm-up block, Two In and One Out
The reaction module of the reaction module of the reaction module of structure, single-entry single-out structure, Two In and One Out structure is anti-for mixing after preheating
It answers, the reaction module of single-entry single-out structure is for extending reaction time.The micro passage reaction used includes warm-up block
Group, reaction module group and cooling module, warm-up block are connected with reaction module group, and reaction module group is connected with cooling module, in advance
Thermal modules group includes a warm-up block or more than two in parallel warm-up blocks, reaction module group include a reaction module or
More than two concatenated reaction modules, cooling module are single-entry single-out individual module；Material 1 enters preheating by mashing pump A
Module 1, warm-up block 1 are connected with reaction module 2；Material 2 enters reaction module 2 by gas flowmeter B.
The present invention will be further described combined with specific embodiments below, but the present invention should not be limited by the examples.
Embodiment 1: present embodiments providing a kind of synthesis of micro passage reaction according to the method for promise Gray's intermediate, specific to walk
It is rapid as follows:
1) weighs raw material 4- nitro-phenylamino t-butyl formate 300g dissolution with the anhydrous methanol of 5L, is then added
Palladium-Pd/carbon catalyst that palladium (Pd) mass content of 15g is 5%, is sufficiently stirring and mixing to form material I, material I is delivered to micro- logical
It is preheated in the warm-up block 1 of road reactor, the reaction module group of micro passage reaction is entered after preheating.
2) hydrogen is delivered to the material I of the reaction module group of micro passage reaction and step 1) after preheating anti-by
Module group is answered to be reacted, in which: the flow velocity for adjusting mashing pump makes the flow velocity 30.0g/min of material I, adjusts H2Gas flow
The flow velocity of meter is 630ml/min, and the molar ratio of raw material 4- nitro-phenylamino t-butyl formate and hydrogen is 1:3.2, reaction temperature
Degree is 60 DEG C, and the temperature of cooling module is 20 DEG C, and the residence time of reaction is 32s, reaction pressure 1.5MPa, is collected from cooling
The reaction solution of the outlet of module 6 outflow, is post-processed, and the post-processing, which refers to, is recovered by filtration catalyst, and vacuum distillation recycling is molten
Then residue is added into the water of 1.2L for agent, adds the concentrated hydrochloric acid of 120ml, and active carbon 30g is added in stirring and dissolving, rises
Temperature is to 40 DEG C of stirring 1h, and filtering, pH=8.0~9.0 of the filtrate NaOH solution regulation system of 1mol/L, heat preservation is stirred at room temperature
1h is mixed, is filtered, filter cake is washed with water, is obtained after being dried in vacuo 10 hours at 50 DEG C according to promise Gray intermediate (4- aminophenyl) amino
T-butyl formate 224.67g, yield 85.67%, purity 99.59%.
Embodiment 2: micro passage reaction synthesizes the method according to promise Gray's intermediate.
1) weighs raw material 4- nitro-phenylamino t-butyl formate 300g dissolution with the dehydrated alcohol of 5L, is then added
Palladium-zeolite catalyst that palladium (Pd) mass content of 12g is 3%, is sufficiently stirring and mixing to form material I, material I is delivered to micro-
It is preheated in the warm-up block 1 of channel reactor, the reaction module group of micro passage reaction is entered after preheating.
2) hydrogen is delivered to the material I of the reaction module group of micro passage reaction and step 1) after preheating anti-by
Module group is answered to be reacted, in which: the flow velocity for adjusting mashing pump makes the flow velocity 30.0g/min of material I, adjusts H2Gas flow
The flow velocity of meter is 580ml/min, and the molar ratio of raw material 4- nitro-phenylamino t-butyl formate and hydrogen is 1:3.0, reaction temperature
Degree is 70 DEG C, and the temperature of cooling module is 25 DEG C, and the residence time of reaction is 34s, reaction pressure 1.5MPa, is collected from cooling
The reaction solution of the outlet of module 6 outflow, is post-processed, and the post-processing, which refers to, is recovered by filtration catalyst, and vacuum distillation recycling is molten
Then residue is added into the water of 1.2L for agent, adds the concentrated hydrochloric acid of 120ml, and active carbon 30g is added in stirring and dissolving, rises
Temperature is to 40 DEG C of stirring 1h, and filtering, pH=8.0~9.0 of the filtrate NaOH solution regulation system of 1mol/L, heat preservation is stirred at room temperature
1h is mixed, is filtered, filter cake is washed with water, is obtained after being dried in vacuo 10 hours at 50 DEG C according to promise Gray intermediate (4- aminophenyl) amino
T-butyl formate 227.08g, yield 86.59%, purity 97.41%.
Embodiment 3: micro passage reaction synthesizes the method according to promise Gray's intermediate.
1) weighs raw material 4- nitro-phenylamino t-butyl formate 300g dissolution with the dehydrated alcohol of 5L, is then added
Palladium-molecular sieve catalyst that palladium (Pd) the Pt mass content of 10g is 5%, is sufficiently stirring and mixing to form material I, material I is conveyed
It is preheated into the warm-up block 1 of micro passage reaction, the reaction module group of micro passage reaction is entered after preheating.
2) hydrogen is delivered to the material I of the reaction module group of micro passage reaction and step 1) after preheating anti-by
Module group is answered to be reacted, in which: the flow velocity for adjusting mashing pump makes the flow velocity 35.0g/min of material I, adjusts H2Gas flow
The flow velocity of meter is 800ml/min, and the molar ratio of raw material 4- nitro-phenylamino t-butyl formate and hydrogen is 1:3.5, reaction temperature
Degree is 80 DEG C, and the temperature of cooling module is 30 DEG C, and the residence time of reaction is 36s, reaction pressure 1.0MPa, is collected from cooling
The reaction solution of the outlet of module 6 outflow, is post-processed, and the post-processing, which refers to, is recovered by filtration catalyst, and vacuum distillation recycling is molten
Then residue is added into the water of 1.2L for agent, adds the concentrated hydrochloric acid of 120ml, and active carbon 30g is added in stirring and dissolving, rises
Temperature is to 40 DEG C of stirring 1h, and filtering, pH=8.0~9.0 of the filtrate NaOH solution regulation system of 1mol/L, heat preservation is stirred at room temperature
1h is mixed, is filtered, filter cake is washed with water, is obtained after being dried in vacuo 10 hours at 50 DEG C according to promise Gray intermediate (4- aminophenyl) amino
T-butyl formate 233.50g, yield 89.04%, purity 99.11%.
Embodiment 4: micro passage reaction synthesizes the method according to promise Gray's intermediate.
1) weighs raw material 4- nitro-phenylamino t-butyl formate 300g dissolution with the anhydrous methanol of 5L, is then added
Palladium-Pd/carbon catalyst that palladium (Pd) mass content of 30g is 2%, is sufficiently stirring and mixing to form material I, material I is delivered to micro- logical
It is preheated in the warm-up block 1 of road reactor, the reaction module group of micro passage reaction is entered after preheating.
2) hydrogen is delivered to the material I of the reaction module group of micro passage reaction and step 1) after preheating anti-by
Module group is answered to be reacted, in which: the flow velocity for adjusting mashing pump makes the flow velocity 42.0g/min of material I, adjusts H2Gas flow
The flow velocity of meter is 870ml/min, and the molar ratio of raw material 4- nitro-phenylamino t-butyl formate and hydrogen is 1:3.2, reaction temperature
Degree is 90 DEG C, and the temperature of cooling module is 20 DEG C, and the residence time of reaction is 20s, reaction pressure 0.8MPa, is collected from cooling
The reaction solution of the outlet of module 6 outflow, is post-processed, and the post-processing, which refers to, is recovered by filtration catalyst, and vacuum distillation recycling is molten
Then residue is added into the water of 1.2L for agent, adds the concentrated hydrochloric acid of 120ml, and active carbon 30g is added in stirring and dissolving, rises
Temperature is to 40 DEG C of stirring 1h, and filtering, pH=8.0~9.0 of the filtrate NaOH solution regulation system of 1mol/L, heat preservation is stirred at room temperature
1h is mixed, is filtered, filter cake is washed with water, is obtained after being dried in vacuo 10 hours at 50 DEG C according to promise Gray intermediate (4- aminophenyl) amino
T-butyl formate 234.95g, yield 89.59%, purity 99.50%.
Embodiment 5: micro passage reaction synthesizes the method according to promise Gray's intermediate.
1) weighs raw material 4- nitro-phenylamino t-butyl formate 300g dissolution with the anhydrous methanol of 5L, is then added
Palladium-Pd/carbon catalyst that palladium (Pd) mass content of 15g is 0.5%, is sufficiently stirring and mixing to form material I, material I is delivered to micro-
It is preheated in the warm-up block 1 of channel reactor, the reaction module group of micro passage reaction is entered after preheating.
2) hydrogen is delivered to the material I of the reaction module group of micro passage reaction and step 1) after preheating anti-by
Module group is answered to be reacted, in which: the flow velocity for adjusting mashing pump makes the flow velocity 18.0g/min of material I, adjusts H2Gas flow
The flow velocity of meter is 400ml/min, and the molar ratio of raw material 4- nitro-phenylamino t-butyl formate and hydrogen is 1:3.5, reaction temperature
Degree is 100 DEG C, and the temperature of cooling module is 25 DEG C, and the residence time of reaction is 50s, reaction pressure 1.5MPa, is collected from drop
The reaction solution of the warm outlet of module 6 outflow, is post-processed, and the post-processing, which refers to, is recovered by filtration catalyst, vacuum distillation recycling
Then residue is added into the water of 1.2L for solvent, adds the concentrated hydrochloric acid of 120ml, and active carbon 30g is added in stirring and dissolving,
40 DEG C of stirring 1h are warming up to, are filtered, filtrate pH=8.0~9.0 of the NaOH solution regulation system of 1mol/L are kept the temperature at room temperature
1h, filtering are stirred, filter cake is washed with water, is obtained after being dried in vacuo 10 hours at 50 DEG C according to promise Gray intermediate (4- aminophenyl) ammonia
Base t-butyl formate 228.78g, yield 87.24%, purity 98.41%.
Embodiment 6: micro passage reaction synthesizes the method according to promise Gray's intermediate.
1) weighs raw material 4- nitro-phenylamino t-butyl formate 300g dissolution with the dehydrated alcohol of 5L, is then added
Palladium-resin catalyst that palladium (Pd) mass content of 15g is 2%, is sufficiently stirring and mixing to form material I, material I is delivered to micro-
It is preheated in the warm-up block 1 of channel reactor, the reaction module group of micro passage reaction is entered after preheating.
2) hydrogen is delivered to the material I of the reaction module group of micro passage reaction and step 1) after preheating anti-by
Module group is answered to be reacted, in which: the flow velocity for adjusting mashing pump makes the flow velocity 45.0g/min of material I, adjusts H2Gas flow
The flow velocity of meter is 870ml/min, and the molar ratio of raw material 4- nitro-phenylamino t-butyl formate and hydrogen is 1:3.0, reaction temperature
Degree is 110 DEG C, and the temperature of cooling module is 20 DEG C, and the residence time of reaction is 12s, reaction pressure 0.5MPa, is collected from drop
The reaction solution of the warm outlet of module 6 outflow, is post-processed, and the post-processing, which refers to, is recovered by filtration catalyst, vacuum distillation recycling
Then residue is added into the water of 1.2L for solvent, and the concentrated hydrochloric acid of 120ml is added, and active carbon 30g is added in stirring and dissolving, rises
Temperature is to 40 DEG C of stirring 1h, and filtering, pH=8.0~9.0 of the filtrate NaOH solution regulation system of 1mol/L, heat preservation is stirred at room temperature
1h is mixed, is filtered, filter cake is washed with water, is obtained after being dried in vacuo 10 hours at 50 DEG C according to promise Gray intermediate (4- aminophenyl) amino
T-butyl formate 220.08g, yield 83.92%, purity 97.26%.
Embodiment 7: micro passage reaction synthesizes the method according to promise Gray's intermediate.
1) weighs raw material 4- nitro-phenylamino t-butyl formate 300g dissolution with the anhydrous methanol of 5L, is then added
Palladium-zeolite catalyst that palladium (Pd) mass content of 12g is 5%, is sufficiently stirring and mixing to form material I, material I is delivered to micro-
It is preheated in the warm-up block 1 of channel reactor, the reaction module group of micro passage reaction is entered after preheating.
2) hydrogen is delivered to the material I of the reaction module group of micro passage reaction and step 1) after preheating anti-by
Module group is answered to be reacted, in which: the flow velocity for adjusting mashing pump makes the flow velocity 25.0g/min of material I, adjusts H2Gas flow
The flow velocity of meter is 480ml/min, and the molar ratio of raw material 4- nitro-phenylamino t-butyl formate and hydrogen is 1:3.0, reaction temperature
Degree is 120 DEG C, and the temperature of cooling module is 20 DEG C, and the residence time of reaction is 40s, reaction pressure 0.8MPa, is collected from drop
The reaction solution of the warm outlet of module 6 outflow, is post-processed, and the post-processing, which refers to, is recovered by filtration catalyst, vacuum distillation recycling
Then residue is added into the water of 1.2L for solvent, and the concentrated hydrochloric acid of 120ml is added, and active carbon 30g is added in stirring and dissolving, rises
Temperature is to 40 DEG C of stirring 1h, and filtering, pH=8.0~9.0 of the filtrate NaOH solution regulation system of 1mol/L, heat preservation is stirred at room temperature
1h is mixed, is filtered, filter cake is washed with water, is obtained after being dried in vacuo 10 hours at 50 DEG C according to promise Gray intermediate (4- aminophenyl) amino
T-butyl formate 212.92g, yield 81.19%, purity 95.21%.
One, influence of the reaction temperature to yield and purity according to promise Gray's intermediate is investigated:
Embodiment 8: micro passage reaction synthesizes the method according to promise Gray's intermediate, the specific steps are as follows:
1) weighs raw material 4- nitro-phenylamino t-butyl formate 300g dissolution with the anhydrous methanol of 5L, is then added
The Pd- Pd/carbon catalyst that palladium (Pd) mass content of 15g is 5%, is sufficiently stirring and mixing to form material I, material I is delivered to micro- logical
It is preheated in the warm-up block 1 of road reactor, the reaction module group of micro passage reaction is entered after preheating.
2) hydrogen is delivered to the material I of the reaction module group of micro passage reaction and step 1) after preheating anti-by
Module group is answered to be reacted, in which: the flow velocity for adjusting mashing pump makes the flow velocity 30.0g/min of material I, adjusts H2Gas flow
The flow velocity of meter is 630ml/min, and the molar ratio of raw material 4- nitro-phenylamino t-butyl formate and hydrogen is 1:3.2, reaction temperature
Degree is 90 DEG C, and the temperature of cooling module is 25 DEG C, and the residence time of reaction is 25s, reaction pressure 1.2MPa, is collected from cooling
The reaction solution of the outlet of module 6 outflow, is post-processed, and the post-processing, which refers to, is recovered by filtration catalyst, and vacuum distillation recycling is molten
Then residue is added into the water of 1.2L for agent, and the concentrated hydrochloric acid of 120ml is added, and active carbon 30g, heating is added in stirring and dissolving
To 40 DEG C of stirring 1h, filter, filtrate pH=8.0~9.0 of the NaOH solution regulation system of 1mol/L, at room temperature insulated and stirred
1h, filtering, filter cake are washed with water, are obtained after being dried in vacuo 10 hours at 50 DEG C according to promise Gray intermediate (4- aminophenyl) amino first
Tert-butyl acrylate 234.74g, yield 89.51%, purity 99.49%.
Embodiment 9: repeating embodiment 8, and the present embodiment and the difference of embodiment 8 are, step 2) is described in the present embodiment
Reaction temperature is 60 DEG C.
Embodiment 10: repeating embodiment 8, and the present embodiment and the difference of embodiment 8 are, step 2) is described in the present embodiment
Reaction temperature is 70 DEG C.
Embodiment 11: repeating embodiment 8, and the present embodiment and the difference of embodiment 8 are, step 2) is described in the present embodiment
Reaction temperature is 80 DEG C.
Embodiment 12: repeating embodiment 8, and the present embodiment and the difference of embodiment 8 are, step 2) is described in the present embodiment
Reaction temperature is 100 DEG C.
Embodiment 13: repeating embodiment 8, and the present embodiment and the difference of embodiment 8 are, step 2) is described in the present embodiment
Reaction temperature is 110 DEG C.
Embodiment 14: repeating embodiment 8, and the present embodiment and the difference of embodiment 8 are, step 2) is described in the present embodiment
Reaction temperature is 120 DEG C.
Embodiment 8 to embodiment 14 is the influence for investigating reaction temperature to yield and purity according to promise Gray's intermediate, real
Test that the results are shown in Table 1.
This method is obtained at a temperature of 1 differential responses of table counts according to the yield and purity of promise Gray's intermediate
| Experimental group | Reaction temperature | Yield (%) | Purity (%) |
| Embodiment 8 | 90℃ | 89.51 | 99.49 |
| Embodiment 9 | 60℃ | 85.24 | 96.52 |
| Embodiment 10 | 70℃ | 86.71 | 97.39 |
| Embodiment 11 | 80℃ | 88.93 | 99.04 |
| Embodiment 12 | 100℃ | 87.15 | 98.36 |
| Embodiment 13 | 110℃ | 84.09 | 97.18 |
| Embodiment 14 | 120℃ | 81.31 | 95.30 |
As shown in Table 1, reaction temperature is very big to the yield and impurities affect of target product, in the relatively low feelings of reaction temperature
Raw material has a residue under condition, and temperature is excessively high that there will be the generations of a large amount of by-product, therefore reaction temperature is the key that step reaction
Technological parameter, reaction temperature are 90 DEG C the most suitable.
Two, the recycled efficiency to investigate catalyst:
On the basis of embodiment 8, high spot review recycled multiple Pd- Pd/carbon catalyst is received with reacting for this test
Relationship between rate, product purity, the specific method is as follows:
By taking palladium-Pd/carbon catalyst Pd/C is catalyst as an example, 8 recycled experiments are carried out altogether, it may be assumed that use catalyst Pd/C
It is to apply test for the first time in embodiment 8, is then re-used for the catalyst Pd/C recycled after applying test for the first time
Embodiment 8 as applies test for the second time, and the catalyst Pd/C recycled after applying test for the second time is re-used for implementing
Example 8 as applies test for the third time, and so on, eight recycled experiments are carried out altogether；Test is applied every time according to implementation
Example 8 carries out, and guarantees in the identical situations of key process parameters such as reaction temperature, catalyst amount, hydrogen usage, residence time,
Recycled experimental result is as shown in table 2:
Table 2Pd/C catalyst circulation applies experiment
The results show that all not having by the conversion ratio that the Pd- Pd/carbon catalyst of multiple recycled reacts in use
There is apparent decline, illustrate that catalyst still has very high activity by 8 recycleds, can guarantee that higher product is received
Rate and purity.
Comparative example 1: this comparative example provides a kind of production of conventional high-pressure reaction kettle according to the method for promise Gray's intermediate, specifically
Method is as follows:
4- nitro-phenylamino t-butyl formate 150g is added into the high-pressure stirring reaction kettle of 5L, is then added 2.5L's
Anhydrous methanol the Pd- Pd/carbon catalyst that the Pd mass content of 30g is 5% is added after stirring and dissolving, to high pressure after being thoroughly mixed
H is passed through in kettle2, guarantee that the pressure in reaction kettle is 3.0MPa, be warming up to 120 DEG C and insulation reaction 10 hours or so, reacted
Bi Jiangzhi room temperature is post-processed, and the post-processing, which refers to, is recovered by filtration catalyst, and vacuum distillation recovered solvent then will be remaining
Object is added in 600mL water, adds the concentrated hydrochloric acid of 60ml, and stirring and dissolving is added active carbon 15g, is warming up to 40 DEG C of stirring 1h, mistake
Filter, filtrate pH=8.0~9.0 of the NaOH solution regulation system of 1mol/L, insulated and stirred 1h, filtering, filter cake are used at room temperature
Water washing obtains after being dried in vacuo 10 hours at 50 DEG C according to promise Gray intermediate 94.87g, yield 72.35%, purity
87.93%.
By being compared the embodiment of the present invention with comparative example: the micro passage reaction reaction time only needs 30s
Left and right, and the reaction time of autoclave needs 10h；And it is sufficiently bulky that reaction kettle holds liquid, prolonged high-pressure hydrogenation reaction ten
Point danger, and micro passage reaction is since liquid holdup is small (less than 50ml), even if there is a small amount of hydrogen leak to there will not be too big danger
Danger；It will lead to raw material since the reaction time is too long and different degrees of high temperature degradation occur for product, reaction yield is obviously relatively low, and
Micro passage reaction can cool down after the completion of main reaction online at any time since reaction time control is exactly accurate, the yield of product
It is all had been improved with purity.Therefore, micro passage reaction fast, liquid holdup with reaction speed compared with conventional high-pressure reaction kettle
The advantages that small, safety and environmental protection, the content of over-hydrogenation by-product can greatly reduce during the reaction, the yield of final products
High, quality is more preferably.
Although the present invention has been disclosed in the preferred embodiment as above, it is not intended to limit the invention, any to be familiar with this
The people of technology can do various changes and modification, therefore protection of the invention without departing from the spirit and scope of the present invention
Range should subject to the definition of the claims.
Claims (10)
1. a kind of micro passage reaction synthesis is according to the method for promise Gray's intermediate, which is characterized in that steps are as follows:
1) raw material 4- nitro-phenylamino t-butyl formate is added in organic solvent and is dissolved, precious metal palladium load is then added and urges
Material I is delivered in the warm-up block of micro passage reaction and preheats as material I by agent, the mixture of acquisition, preheats laggard
Enter reaction module group；The concentration of the 4- nitro-phenylamino t-butyl formate in organic solvent be 0.2mol/L~
0.3mol/L；The mass ratio of the 4- nitro-phenylamino t-butyl formate and precious metal palladium supported catalyst be 1:(0.01~
0.10)；
2) hydrogen is delivered to the material I of the reaction module group and step 1) of micro passage reaction after preheating in reaction module
Group is reacted, and the reaction solution flowed out from cooling module is collected, and post-processing is obtained according to promise Gray intermediate (4- aminophenyl) amino
T-butyl formate；The molar ratio of 4- nitro-phenylamino t-butyl formate and hydrogen is 1:(3.0~3.5 in the material I).
2. micro passage reaction synthesis according to claim 1 is according to the method for promise Gray's intermediate, which is characterized in that step
1) organic solvent is methanol or ethyl alcohol.
3. micro passage reaction synthesis according to claim 1 is according to the method for promise Gray's intermediate, which is characterized in that step
1) the precious metal palladium supported catalyst described in is palladium-Pd/carbon catalyst, palladium-molecular sieve catalyst, palladium-zeolite catalyst, palladium-resin
One of catalyst or a variety of compositions；Wherein precious metal palladium quality accounts for the 0.5%~5% of catalyst gross mass.
4. micro passage reaction synthesis according to claim 1 is according to the method for promise Gray's intermediate, which is characterized in that step
2) pressure of the reaction is 0.5MPa~1.5MPa.
5. micro passage reaction synthesis according to claim 1 is according to the method for promise Gray's intermediate, which is characterized in that step
2) temperature of the reaction is 60 DEG C~120 DEG C.
6. micro passage reaction synthesis according to claim 5 is according to the method for promise Gray's intermediate, which is characterized in that step
2) temperature of the reaction is 90 DEG C.
7. micro passage reaction synthesis according to claim 1 is according to the method for promise Gray's intermediate, which is characterized in that step
2) temperature of the cooling module is 20 DEG C~30 DEG C.
8. micro passage reaction synthesis according to claim 1 is according to the method for promise Gray's intermediate, which is characterized in that step
2) total residence time of the material I and hydrogen in reaction module group is 10s~50s.
9. micro passage reaction synthesis according to claim 1 is according to the method for promise Gray's intermediate, which is characterized in that step
1) concentration of 4- nitro-phenylamino t-butyl formate in organic solvent is 0.25mol/L in；4- nitro-phenylamino formic acid
The mass ratio of the tert-butyl ester and precious metal palladium supported catalyst is 1:0.05.
10. micro passage reaction synthesis according to claim 1 is according to the method for promise Gray's intermediate, which is characterized in that step
It is rapid 2) described in material I the molar ratio of 4- nitro-phenylamino t-butyl formate and hydrogen be 1:3.2.
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| CN108003154A (en) * | 2017-12-13 | 2018-05-08 | 黑龙江鑫创生物科技开发有限公司 | A kind of method using micro passage reaction synthesis paliperidone intermediate |
| CN108017575A (en) * | 2018-01-26 | 2018-05-11 | 黑龙江鑫创生物科技开发有限公司 | A kind of method that micro passage reaction synthesis gram azoles replaces Buddhist nun's intermediate |
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